Joshua R. Huot, PhD

Cancer remains a leading cause of death worldwide and results in over 600,000 deaths annually in the United States alone. Cancer patients frequently develop cachexia, a wasting syndrome which lowers treatment tolerance, worsens quality of life and survival in cancer patients, and is responsible for upwards of 30% of all cancer-related deaths. Despite that most cancer patients develop cachexia, it remains an underserved research area, with no currently approved prevention or treatment options. Cachexia is classically defined as muscle loss with or without fat loss. However, in recent years, the systemic nature and nuanced phenotype that accompanies cachexia has become quite clear. This has reshaped our lab’s research agenda, which seeks to promote paradigm shifts in the way we approach cachexia as a field moving forward. 

The Huot Lab currently focuses on the following:

1) Mechanisms driving the onset of muscle weakness caused by cancer and chemotherapy

Most cachexia research to date has placed focus on the mechanisms of muscle wasting, yet emerging evidence suggests that weakness precedes wasting and thus may be an early prognosticator of disease progression. In support of this, our evidence indicates that cancer and chemotherapy impair motor unit connectivity and muscle function before the onset of wasting, suggesting that neuromuscular dysfunction is an early indicator of cachexia development. Thus, we are seeking to understand the mechanisms underlying the onset of cancer- and chemotherapy-induced muscle weakness. This work focuses on identifying the neuromuscular junction as a strategy to prevent cancer- and chemotherapy-induced muscle weakness. 

2) Mechanisms underlying persistent weakness and fatigue experienced during cancer survivorship

Advancements in cancer detection, treatment, and resection have robustly cancer survivorship. Indeed, there are nearly 18 million cancer survivors in the US today, however muscle weakness and fatigue can persist for years, greatly inhibiting their quality of life. Investigations into the underlying causes of persistent weakness in cancer survivors remain understudied and underserved, leaving a critical research gap on the clinical sequelae of cancer and its treatments. We have developed models of tumor resection allowing us to study persistent neuromuscular impairment and weakness in murine cancer survivors. This work will focus on identifying and developing therapeutic targets to improve muscle function during cancer survivorship. 

3) Inter-tissue communication: Investigating the Liver as a mediator of musculoskeletal wasting

The mechanisms driving cancer cachexia have been studied for over thirty years, yet most research has focused on single organ perturbations, placing emphasis on tumor-tissue crosstalk, and ignoring the role of inter-tissue communication. In addition to musculoskeletal wasting, cancer also perturbs hepatic function, causing genomic and metabolic shifts in the liver. Aside from its role in energy metabolism, the liver provides endocrine functions via its secreted cytokines (i.e. hepatokines). We have shown that liver metastases exacerbate cachexia and have identified altered hepatokine secretion in response to cancer and chemotherapy, suggesting the liver may contribute to cachexia progression. This work seeks to understand the liver’s role in mediating musculoskeletal wasting during the progression of cachexia. We hope that this research will reveal novel interventions to combat against cancer cachexia.